Clinical evaluation of gemcitabine in dogs with spontaneously occurring malignancies

We conducted a clinical evaluation of gemcitabine in 19 dogs with spontaneously occurring malignancies. The principal objectives of this study were to characterize toxicity and seek preliminary evidence of antitumor activity of gemcitabine administered every 2 weeks (biweekly) as a 30-minute IV infusion. A total of 64 doses, ranging from 300 mg/m2 to 675 mg/m2, were administered during the initial 8-week evaluation period, and an additional 131 doses were administered during the extended evaluation period. The total cumulative dose for the 10 dogs receiving gemcitabine in the extended evaluation period ranged from 1,500 mg/m2 to 24,300 mg/m2. Clinical evidence of toxicity was minimal. Cumulative myelosuppression was not apparent. Unexplained retinal hemorrhages occurred in 1 dog. No complete or partial remissions were observed during the initial evaluation period; however, objective responses were observed in 2 dogs during the extended evaluation period. Gemcitabine is a promising new chemotherapeutic agent that can be used safely in dogs with cancer. Biweekly administration of doses of 675 mg/m2 IV results in minimal and acceptable toxicity.     

Hepatotoxicity associated with CCNU (lomustine) chemotherapy in dogs

One hundred seventy-nine tumor-bearing dogs were treated with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) between 1995 and 2001. CCNU was given as a single dose of 50-110 mg/m2 body surface area PO. Treatment interval varied, but the minimal interval between CCNU doses was 3 weeks. After treatment, 11 dogs (6.1%) developed hepatic toxicity. The median number of CCNU doses and the median total cumulative CCNU dose were significantly higher in dogs that developed hepatic toxicity (4 doses; 350 mg/m2) than in dogs without hepatic damage (3 doses; 230 mg/m2). Median duration to detection of hepatic toxicity from the last dose of CCNU was 11 weeks (range 2-49 weeks). Common biochemical abnormalities were abnormally high serum liver enzyme activities and hypoalbuminemia. Six dogs with CCNU-associated hepatic toxicity had ascites, and 3 dogs had concurrent pleural effusion. Serum concentrations of bile acids were abnormally high in 4 of 5 dogs tested. Percutaneous ultrasound-guided liver biopsies were performed in 10 dogs, and findings were nonspecific and chronic in nature. Seven dogs were euthanized because of progressive liver failure, and their median survival from diagnosis of liver disease was 9 weeks. Three dogs died of other causes and 1 dog of unknown cause. Although clinical signs resolved in 3 dogs, biochemical abnormalities and histopathologic lesions persisted 4 to 38 months from the time of diagnosis of liver disease. Our findings suggest that CCNU can cause delayed, cumulative dose-related, chronic hepatotoxicity that is irreversible and can be fatal.     

Single agent gemcitabine chemotherapy in dogs with spontaneously occurring lymphoma

BACKGROUND: Gemcitabine has been shown to be effective as a single agent in a variety of tumors including nonHodgkin's lymphoma. Its use in veterinary medicine has been limited and to date this drug has not been used as a first-line therapy in dogs with lymphoma. HYPOTHESIS: Gemcitabine as a single agent may be efficacious in dogs presented for the first time with lymphoma. ANIMALS: Twenty-four dogs with spontaneously occurring lymphoma. METHODS: All dogs were clinically staged and given gemcitabine at 400 mg/m(2) over a 30-minute intravenous infusion weekly for 3 weeks and then given 1 week off treatment before starting a second cycle. RESULTS: A single dose of gemcitabine lowered both neutrophil count (decrease in mean neutrophil count from 10,640 cells/ microL to 3,140 cells/microL) and platelet count (decrease in mean platelet count from 201,290 cells/microL to 139,190 cells/microL) 7 days after administration. Consequently gemcitabine dosage was reduced at the second treatment in 8 of 21 dogs or a dose delay of 1-7 days and a reduction of dosage was used in 7 of 21 dogs. Seven dogs completed the assigned 4-week cycle. Two of these dogs had progressive disease and 5 had stable disease. No objective responses were seen in dogs treated with a second cycle of gemcitabine. CONCLUSIONS AND CLINICAL IMPORTANCE: Gemcitabine administration as a single agent resulted in hematologic toxicity and did not reduce lymphoma burden. If gemcitabine is to be used in veterinary medicine, additional prospective pharmacologic studies should be done to determine the appropriate dosage, regimen, and schedule of use before it can be recommended for use in the treatment of dogs with lymphoma as a single agent.     

An open-label, dose-escalating phase I study of elsamitrucin (SPI 28090) in treatment of malignant solid tumors in dogs

Background: Elsamitrucin, the most potent topoisomerase II inhibitor available, is unique in that it does not cause neutropenia or cardiotoxicosis. It has antitumor activity in human patients with relapsed or refractory non‐Hodgkin's lymphoma. Objectives: To determine the maximum tolerated dose (MTD), safety, and toxicity of elsamitrucin when administered to tumor‐bearing dogs and to evaluate the incidence and severity of adverse events. Animals: Twenty client‐owned dogs with spontaneous malignant solid tumors or lymphoma that were refractory to, or for which the owner declined, conventional therapy were enrolled. Methods: Prospective, open‐label, single‐agent study. Escalating doses of elsamitrucin were administered once weekly IV for up to 16 weeks in a modified 3 + 3 Phase I design. The starting dose was 0.06 mg/kg with escalation to 0.08 and 0.09 mg/kg. Dogs that remained on the study were monitored for evidence of toxicoses for at least 4 weeks and for survival every 2 months. Results: Serious adverse events (SAEs) possibly attributable to elsamitrucin include: 1 dog developed heart failure and another developed hepatotoxicosis manifested by increased alanine aminotransferase, alkaline phosphatase, and total bilirubin (0.06 mg/kg dose); 1 dog developed severe anorexia and diarrhea, another developed severe diarrhea alone, and a 3rd dog went into cardiac arrest (0.09 mg/kg dose). A dose of 0.08 mg/kg was well tolerated with no SAEs. Conclusions and Clinical Importance: The MTD and recommended dose for Phase II trials of elsamitrucin is 0.08 mg/kg IV weekly. Elsamitrucin might be considered for combination protocols with myelosuppressive chemotherapy agents.     

Polypoid cystitis in 17 dogs (1978-2001)

Polypoid cystitis is a rare disease of the urinary bladder in dogs characterized by inflammation, epithelial proliferation, and development of a polypoid mass or masses without histopathologic evidence of neoplasia. Medical records of 17 dogs with polypoid cystitis were reviewed to determine the clinical and laboratory features of this disorder and to assess treatment and outcome. Most affected dogs (15/17) were female and presented for evaluation of hematuria or recurrent urinary tract infection (UTI). Proteus spp were the most common bacterial isolates (12/52 or 23.1%) identified when all urine samples obtained for culture at any time during the course study were considered. Other commonly isolated organisms included Escherichia coli , Staphylococcus spp, and Enterococcus spp. Several dogs (7/17) also had cystic calculi at some time during the course of their disease. Most of the masses (11/14) were located cranioventrally in the bladder as opposed to transitional cell carcinoma, which has a predilection for the bladder neck or trigone area. It is unknown whether persistent or recurrent UTI predisposes to polyp formation or if polyps predispose to UTI. Surgery and removal of all polyps was the most efficacious treatment in dogs of this study. The question of whether or not polyps represent preneoplastic lesions remains unanswered and constitutes an area for future investigation.     

Endostatin concentrations in healthy dogs and dogs with selected neoplasms

Endostatin prevents angiogenesis and tumor growth by inhibiting endothelial cell proliferation and migration. The purpose of this study was to determine serum endostatin concentrations in 53 healthy dogs and in 38 dogs with confirmed malignant neoplasms. Endostatin concentration was determined with a competitive enzymatic immunoassay (EIA) with rabbit polyclonal antibody generated against a recombinant canine endostatin protein. Both the presence of cancer and increasing age were associated with increased serum concentration of endostatin. Endostatin concentration in healthy dogs was 87.7 +/- 3.5 ng/mL. Upper and lower limits of the reference range for serum endostatin concentration in healthy dogs were 60 and 113 ng/mL. Dogs with lymphoma (LSA) and hemangiosarcoma (HSA) had endostatin concentrations of 107 +/- 9.3 ng/mL. In conclusion, this study demonstrates that endostatin can be quantified in dogs and that endostatin concentrations are high in dogs with HSA and LSA.     

Cisplatin and doxorubicin toxicosis in dogs with osteosarcoma

Toxicosis associated with doxorubicin and cisplatin administration starting either 2 or 10 days after limb amputation for osteosarcoma was examined retrospectively in dogs. The purpose was to determine whether dosage and timing of chemotherapy affected rates of toxicosis after administration of the 1st treatment. Records of 100 dogs with appendicular osteosarcoma without evidence of metastases or concurrent disease were examined. Dogs received chemotherapy with doxorubicin and cisplatin every 3 weeks for 3 treatments starting 2 days (n = 51) or 10 days (n = 49) after amputation. The dosage of cisplatin was 60 mg/m2 and was given with 6-hour saline diuresis and butorphanol. Doxorubicin was given at 12.5-25 mg/ml during fluid administration. Hematologic data were collected before and weekly after treatment. Client interviews were conducted to assess gastrointestinal toxicosis during the interval between treatments. The reported toxicoses were graded on a scale of 0 to 4. Dogs receiving 25 mg/m2 of doxorubicin experienced greater rates of grade 4 toxicity (67%; n = 6) than dogs in groups receiving 12.5-20 mg/m2 of doxorubicin (< or = 25%; n = 94, P = .03). Dogs in the Day 2 group experienced greater rates (35%) of grade 4 toxicity than dogs in the Day 10 group (12%, P = .007). We concluded that chemotherapy administered 2 days after surgery produced an unacceptable level of toxicoses. except at greatly reduced dosages, and that even with a delay of treatment, 25 mg/m2 of doxorubicin, when given in combination with cisplatin at 60 mg/m2, was too toxic for routine use.     

Clinical evaluation of dietary modification for treatment of spontaneous chronic renal failure in dogs

OBJECTIVE: To determine whether a diet used for dogs with renal failure (renal food [RF]) was superior to an adult maintenance food (MF) in minimizing uremic crises and mortality rate in dogs with spontaneous chronic renal failure. DESIGN: Double-masked, randomized, controlled clinical trial. ANIMALS: 38 dogs with spontaneous chronic renal failure. PROCEDURE: Dogs were randomly assigned to a group fed adult MF or a group fed RF and evaluated for up to 24 months. The 2 groups were of similar clinical, biochemical, and hematologic status. The effects of diets on uremic crises and mortality rate were compared. Changes in renal function were evaluated by use of serial evaluation of serum creatinine concentrations and reciprocal of serum creatinine concentrations. RESULTS: Compared with the MF, the RF had a beneficial effect regarding uremic crises and mortality rate in dogs with mild and moderate renal failure. Dogs fed the RF had a slower decline in renal function, compared with dogs fed the MF. CONCLUSIONS AND CLINICAL RELEVANCE: Dietary modifications are beneficial in minimizing extrarenal manifestations of uremia and mortality rate in dogs with mild and moderate spontaneous chronic renal failure. Results are consistent with the hypothesis that delay in development of uremic crises and associated mortality rate in dogs fed RF was associated, at least in part, with reduction in rate of progression of renal failure.     

A phase I clinical trial evaluating imatinib mesylate (Gleevec) in tumor-bearing cats

A phase I clinical trial evaluating the toxicity of orally-administered imatinib mesylate was performed in 9 tumor-bearing cats. Imatinib is a small molecule, tyrosine kinase inhibitor, which selectively blocks the function of overexpressed proteins associated with various malignancies. Cats included in the study had diagnoses of fibrosarcoma, squamous cell carcinoma, and mast cell tumor, and each cat was staged using CBC and serum biochemistry; urinalysis, thoracic radiographs, and abdominal ultrasonography were performed in some cats. Most cats were treated previously by surgery, radiation therapy, chemotherapy, or some combination of these treatments. None of the cats received any concurrent chemotherapy. Six cats were treated with imatinib mesylate at 1-2 mg/kg PO q24h. Dose escalations were made to 2, 4, and 10 mg/kg PO q24h in 5 cats. Two cats started therapy at 10 mg/kg PO q24h, and 1 cat started therapy at 15 mg/kg PO q24h; all 3 cats remained at these dosages. No signs of toxicity, as evaluated by CBC and serum biochemistry, were noted in 8 of the 9 cats, and minimal gastrointestinal toxicity was observed. Due to the low frequency of adverse effects, further evaluation of imatinib is ongoing at a dosage of 10 mg/kg PO q24h.     

Biochemical analysis of pericardial fluid and whole blood in dogs with pericardial effusion

Studies evaluating pericardial fluid analysis in dogs to determine the etiology of pericardial effusions have yielded conflicting results. The purpose of this prospective study was to compare acid-base status, electrolyte concentrations, glucose, and lactate of pericardial fluid to peripheral blood from dogs with pericardial effusion and to compare these variables between dogs with neoplastic and nonneoplastic pericardial effusion. Acid-base status, electrolyte concentrations, glucose, hematocrit, urea nitrogen, and lactate concentrations were evaluated in peripheral blood samples and in pericardial effusion samples of 41 client-owned dogs with pericardial effusion. Common abnormal findings in the peripheral blood of dogs with pericardial effusion included hyperlactatemia (n = 38 [of 41]; 93%), hyponatremia (n = 25/41; 61%), hyperglycemia (n = 13/41; 32%), and hypermagnesemia (n = 13/41; 32%). Bicarbonate, sodium, ionized calcium, glucose, and hematocrit were all significantly lower in the pericardial fluid compared with peripheral blood, whereas lactate, chloride, and PCO2 were significantly higher in the pericardial fluid. When comparing the concentrations of variables in the pericardial fluid of dogs with neoplasia (n = 28) to those without neoplasia (n = 13), pH, bicarbonate, and chloride were significantly lower in dogs with neoplasia, whereas lactate, hematocrit, and urea nitrogen were significantly higher in the pericardial fluid of dogs with neoplasia. The difference between peripheral and pericardial glucose concentrations was significantly larger in dogs with neoplasia than in dogs without neoplasia. Although differences between variables in dogs with neoplastic and nonneoplastic pericardial effusion were documented, clinical relevance is likely limited by the degree of overlap between the 2 groups.     

Prospective clinical evaluation of serum cardiac troponin T in dogs admitted to a veterinary teaching hospital

The purpose of this study was to measure serum cardiac troponin T (cTnT) with a commercially available human enzyme-linked immunoassay (ELISA) test in various groups of dogs, including those undergoing doxorubicin chemotherapy. Serum samples were obtained from 6 groups of dogs: (1) normal adult dogs (n = 15); (2) dogs with asymptomatic dilated cardiomyopathy (n = 5); (3) dogs with congestive heart failure (n = 10); (4) dogs with untreated neoplasia (n = 20); (5) dogs with skeletal muscle trauma (n = 10); and (6) dogs with neoplasia receiving doxorubicin chemotherapy (n = 4). One serum sample was obtained from each of the normal dogs, those with asymptomatic cardiomyopathy, those with congestive heart failure, and those with untreated neoplasia. Serum samples were obtained serially from the dogs that were undergoing doxorubicin chemotherapy; samples were collected before doxorubicin (30 mg/m2) administration and then 1, 5, 7, and 14 days after administration throughout 6 cycles for a cumulative total dose of 180 mg/m2. All normal dogs, dogs with untreated neoplasia, and dogs with asymptomatic dilated cardiomyopathy had cTnT concentrations below the lower limits of detection for the assay used (<0.05 ng/mL). Detectable concentrations of cTnT were found in 3 dogs with congestive heart failure and in 2 dogs with skeletal muscle trauma. Detectable concentrations also were found in both dogs that had received 180 mg/m2 of doxorubicin. We conclude that dogs with congestive heart failure and those with skeletal muscle trauma and dogs with neoplasia receiving high-dose doxorubicin chemotherapy may have increased serum cTnT concentration, which may be suggestive of myocardial damage.     

Evaluation of a novel tumor vaccine in dogs with hemangiosarcoma

BACKGROUND: Hemangiosarcoma (HSA) is a highly metastatic and often rapidly fatal tumor of dogs. At present, adjuvant chemotherapy is the only proven effective treatment for dogs with HSA, though the benefits from chemotherapy are modest. Administration of immunotherapy together with chemotherapy has also been reported to improve survival in dogs with HSA. Therefore, we evaluated safety and immunologic responses to a novel tumor vaccine administered together with doxorubicin chemotherapy in dogs with different stages of HSA. HYPOTHESIS: That tumor vaccination could be safely and effectively combined with doxorubicin chemotherapy for treatment of dogs with HSA. ANIMALS: Twenty-eight dogs with various stages of HSA were enrolled in the study. METHODS: The HSA vaccine was prepared with lysates of allogeneic canine HSA cell lines mixed with an adjuvant composed of liposome-DNA complexes. Dogs received a series of 8 immunizations administered over a 22-week period, and most also received chemotherapy. Clinical adverse effects were noted, immune responses were measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry, and survival times were calculated. RESULTS: The most common adverse effects observed in vaccinated dogs also treated with doxorubicin chemotherapy were diarrhea and anorexia. Vaccinated dogs were found to mount strong humoral immune responses against a control antigen and, most dogs also mounted antibody responses against canine HSA cells. Thirteen dogs with stage II splenic HSA that received the tumor vaccine plus doxorubicin chemotherapy had an overall median survival time of 182 days. CONCLUSIONS: We conclude that an allogeneic tumor lysate vaccine is safe in dogs with HSA and can elicit humoral immune responses in dogs that are receiving concurrent doxorubicin chemotherapy.     

Dexamethasone, melphalan, actinomycin D, cytosine arabinoside (DMAC) protocol for dogs with relapsed lymphoma

BACKGROUND: In general, treatment of relapsed lymphoma is associated with a lower probability of response and shorter duration of remission. The purpose of this study was to evaluate the efficacy of the combination chemotherapy protocol DMAC (dexamethasone, melphalan, actinomycin D, and cytosine arabinoside) for reinduction of remission in dogs with relapsed lymphoma. HYPOTHESIS: That DMAC would be an effective reinduction protocol for dogs with relapsed lymphoma. ANIMALS: Fifty-four dogs. RESULTS: Seventy-two percent of the dogs achieved remission (44% complete remission [CR] and 28% partial remission [PR]), 11% had stable disease (SD), and 17% had progressive disease (PD). The median remission duration was 61 days (range, 2-467+ days). The median remission durations for dogs with CR, PR, and SD were 112, 44, and 27 days, respectively. Factors that affected the response rate were previous treatment with doxorubicin and an inability to achieve remission with the previous protocol. Thrombocytopenia occurred in 56% of the dogs (grade 1 in 3 dogs, grade 2 in 6 dogs, grade 3 in 7 dogs, and grade 4 in 7 dogs) and neutropenia in 17% of the dogs (grade 2 in 1 dog, grade 3 in 2 dogs, and grade 4 in 4 dogs). Gastrointestinal toxicosis occurred in 22% of the dogs (grades 1 in 5 dogs, grade 2 in 3 dogs, and grade 3 in 1 dog). CONCLUSIONS AND CLINICAL IMPORTANCE: The DMAC protocol is an effective rescue protocol for dogs with relapsed multicentric lymphoma. Although thrombocytopenia is a common manifestation of toxicity, in general, the protocol is well tolerated.     

Retrospective study of orthovoltage radiation therapy for nasal tumors in 42 dogs

Megavoltage radiation therapy currently is the standard of care for dogs with nasal tumors. Some studies report that surgery and adjunctive orthovoltage radiation therapy result in longer control of these tumors than does megavoltage radiation therapy alone. This study reports less effective control of nasal tumors in dogs treated with surgery and orthovoltage radiation than previously observed, supporting the superiority of megavoltage radiation therapy for these tumors. In addition, this study suggests 2 new prognostic indicators for dogs with nasal tumors and describes toxicity associated with surgery and orthovoltage therapy. Forty-two dogs with nasal tumors were treated with surgical cytoreduction and 48 Gy orthovoltage radiation therapy administered in twelve 4-Gy fractions. Median survival was 7.4 months. One- and 2-year survival rates were 37% and 17%, respectively. Dogs with facial deformity had shorter survival than those without deformity (P = .005). Dogs with resolution of clinical signs after treatment had longer survival than those with chronic nasal signs (P = .0001). Acute radiation toxicity was moderate to severe for skin and eye and negligible for oral mucosa. Toxicity healed within 1 month after radiation therapy. Late toxicity was mild, but 70% of evaluable dogs experienced persistent ocular signs. Only 39% of dogs achieved a disease-free period.